title: Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse.
abstract: How the vesicular traffic of signaling molecules contributes to T cell receptor (TCR) signal transduction at the immunological synapse remains poorly understood. In this study, we show that the protein tyrosine kinase Lck, the TCRζ subunit, and the adapter LAT traffic through distinct exocytic compartments, which are released at the immunological synapse in a differentially regulated manner. Lck vesicular release depends on MAL protein. Synaptic Lck, in turn, conditions the calcium- and synaptotagmin-7-dependent fusion of LAT and TCRζ containing vesicles. Fusion of vesicles containing TCRζ and LAT at the synaptic membrane determines not only the nanoscale organization of phosphorylated TCRζ, ZAP70, LAT, and SLP76 clusters but also the presence of phosphorylated LAT and SLP76 in interacting signaling nanoterritories. This mechanism is required for priming IL-2 and IFN-γ production and may contribute to fine-tuning T cell activation breadth in response to different stimulatory conditions.
authors.affiliation: Institut Pasteur, Department of Immunology, Lymphocyte Cell Biology Unit, F-75724 Paris, France.
authors.forename: Helena
authors.initials: H
authors.lastname: Soares
authors.forename: Ricardo
authors.initials: R
authors.lastname: Henriques
authors.forename: Martin
authors.initials: M
authors.lastname: Sachse
authors.forename: Leandro
authors.initials: L
authors.lastname: Ventimiglia
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Alonso
authors.forename: Christophe
authors.initials: C
authors.lastname: Zimmer
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Thoulouze
authors.forename: Andrés
authors.initials: A
authors.lastname: Alcover
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002451:Cell Compartmentation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D005089:Exocytosis / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects / Q000276:immunology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050857:Synaptotagmins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C110810:LAT protein, human; D008565:Membrane Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D050857:Synaptotagmins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D002118:Calcium